Dopamine is an important neurotransmitter both in the central nervous system (CNS), and in the peripheral nervous system, in which it has important roles, inter alia, in controlling the supply of blood to the kidneys and in autonomic ganglion transmission. It has been postulated that dopamine is involved in several diverse neurological and psychological disorders such as Parkinson's disease and psychoses, and published evidence (reviewed by R. A. Wise and P.-P. Rompre in Annual Review of Psychology, 1989, Vol. 40: 191-225) suggests that dopamine also plays a fundamental role in the brain's reward system.
CNS receptors which have a high affinity for dopamine may be divided into two general categories, designated as D-1 receptors and D-2 receptors, based on biochemical and pharmacological differences between the two receptor subtypes, as well as on the molecular biology of dopamine receptors in the CNS. For a thorough review of the classification and function of dopamine receptor subtypes, see C. Kaiser and T. Jain, "Dopamine Receptors: Functions, Subtypes and Emerging Concepts" in Medicinal Research Reviews. Vol 5, pp 145-229 (1985).
Stimulation of the dopamine D-1 receptor by dopamine or a dopamine D-1 receptor agonist causes an increase in the production of the second messenger, 3',5'-cyclic adenosine monophosphate (cAMP), by the enzyme adenylate cyclase, which is mediated by a stimulatory G protein.
The biochemical events which follow stimulation of the D-2 receptor by dopamine or a D-2 receptor agonist are not as well understood, however. Autoreceptors on dopaminergic neurons which have the pharmacological properties of D-2 receptors appear to control the firing rate of these neurons as well as the release of dopamine from the nerve terminals. It is also known that stimulation of the D-2 receptors in the intermediate lobe of the pituitary gland causes a decrease in cAMP production and that stimulation of the D-2 receptors on the mammotrophs of the anterior pituitary gland suppresses prolactin secretion. Also, D-2 receptors on the cholinergic interneurons in the striatum (one of the components of the basal ganglia) regulate the release of acetylcholine from these cells.
The putative roles of the two dopamine receptor subtypes also differ in the various neurological and psychological disorders in which dopamine is believed to be involved. Dopaminergic agents that show receptor subtype selectivity therefore potentially have the advantage of eliciting a desired therapeutic response without less desirable side-effects.
Psychoses are serious psychiatric disorders characterized by abnormal behavior including, inter alia, delusions, hallucinations, violence, mania and serious long-lasting depression. Schizophrenia, which was first identified as a disease of the CNS by Kraepelin and Bleuler in the early 1900's, is the most common psychosis and involves disturbance of thought processes, hallucinations and loss of touch with reality. Since the early 1950's, when Delay and Daniker discovered chlorpromazine to be an effective drug for the treatment of schizophrenia, the use of antipsychotic agents for schizophrenia and other psychoses has become widespread and millions of patients have been treated with them. Unfortunately, the currently-available antipsychotic agents frequently produce undesirable side-effects, including commonly, sedation and hypotension, and most commonly, the so-called extrapyramidal neurological effects that include bizarre involuntary movements and Parkinson-like effects. Because of these often-severe side-effects and the high incidence of patients unresponsive to currently-available drugs, more potent and selective agents are needed.
The pioneering work of Carlsson and others led to the now widely-held dopamine theory of schizophrenia. According to this hypothesis (which is supported by several lines of evidence), schizophrenia is caused by a functional overactivity of dopamine in the brain. Chronic abuse of stimulants, such as amphetamines, which are known to enhance dopaminergic activity in the brain, can lead to a paranoid psychosis that is almost indistinguishable from classic paranoid schizophrenia.
The mechanism-of-action postulated for drugs with anti-schizophrenic activity is the blockade by these compounds of the dopamine receptors, and consequently, the prevention of excess dopamine receptor stimulation. In the mid 1970's it was observed that virtually all of the currently-used antipsychotic agents could displace radiolabeled haloperidol (a dopamine D-2 receptor antagonist) from striatal dopamine receptors with a good correlation between average effective clinical dose and drug binding affinity (I. Creese, D. R. Burt and S. H. Snyder, Science, 1976, 192: 481-483). It has now been reported, based on the results of preliminary testing in animal models, that D-1 dopamine receptor-selective antagonists may show antipsychotic activity without the liability of producing undesirable extrapyramidal effects (R. E. Chipkin et al., J. Pharmacology and Experimental Therapeutics, 1988, 247: 1093-1102).
Recent evidence also suggests that, since dopamine D-1 agonists have proconvulsant activity which is mediated via stimulation of the D-1 receptors (G. Al-Tajir, M. S. Starr and B. S. Starr, European J Pharmacology, 1990, 182: 245-251), D-1 antagonists would block this proconvulsant activity and would, therefore, be useful in treating certain types of seizure disorders.
It has further been reported that animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist, possibly in order to maintain the elevated dopamine levels responsible for cocaine's euphorigenic and reinforcing properties. Because of this correlation, dopamine antagonists are potentially also useful for the treatment of drug abuse and other addictive behavior disorders.
Although no dopamine D-1 antagonists are currrently being marketed for the indications discussed above, the therapeutic potential of this class of compounds is widely recognized, see, for example, a review article by J. L. Waddington in General Pharmacology, 1988, 19: 55-60.
1-Substituted 2,3,4,5-tetrahydro-1H-3-benzazepines, especially compounds with a phenyl ring as the 1-substituent, have been described previously as having dopamine D-1 receptor blocking activity. J. Weinstock et al., in Drugs of the Future, 1985, 10: 645-697, discuss the profound effect that 1-phenyl substituents have on the dopaminergic activity of certain types of benzazepines. J. G. Berger, W. K. Chang and M. Peters in International Patent Application Number WO 88/07526, published Oct. 6, 1988, disclose certain 1-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines, including one 1-spirocyclopentane benzazepine derivative, as useful in the treatment of psychoses, depression and pain.